Field
Agents are needed for treating diseases and disorders related to aberrant function of calcium-activated chloride channels, including, for example, increased intestinal fluid secretion, secretory diarrhea, asthma, and cystic fibrosis. Small molecule compounds that are potent inhibitors of chloride conductance via calcium-activated chloride channels and methods for identifying such compounds are described herein.
Description of the Related Art
Diarrheal disease in children is a global health concern: approximately four billion cases among children occur annually, resulting in two million deaths. Antibiotics are routinely used to treat diarrhea; however, the antibiotics are ineffective for treating many pathogens, and the use of these drugs contributes to development of antibiotic resistance in other pathogens.
Calcium-activated chloride channels (CaCCs) are believed to provide an important route for chloride (Cl−) and fluid secretion in secretory diarrheas. Excess transepithelial salt and water transport by one or more CaCCs may be caused by certain drugs (e.g., antiretrovirals, chemotherapeutics) and viruses (see, e.g., Lorrot et al., Virol. J. 4:31 (2007); Morris et al., Am. J. Physiol. 277:G431-44 (1999); Rufo et al., Am. J. Physiol. 264:C998-1008 (2004); Schultheiss et al., Eur. J. Pharmacol. 546:161-70 (2006); Takahashi et al., J. Med. Microbiol. 49:801-10 (2000); Schultheiss et al., J. Membr. Biol. 204:117-27 (2005); Gyömörey et al., Pflugers Arch. 443 Suppl 1:S103-6 (2001); Kidd et al., Annu. Rev. Physiol. 62:493-513 (2000); Barrett et al., Annu. Rev. Physiol. 62:535-72 (2000)). The morbidity and mortality associated with secretory diarrhea indicate an imperative need for potent inhibitors of CaCCs.
In addition, CaCCs are believed to provide an important route for chloride (Cl−) and fluid secretion in pulmonary diseases and disorders. For example, smooth muscle CaCCs have been implicated in the pathophysiology of asthma (see, e.g., Bolton et al., J. Physiol. 570:5-11 (2006); Farthing, Dig. Dis. 24:47-58 (2006); Thiagarajah et al., Trends Pharmacol. Sci. 26, 172-75 (2005))). Airway CaCCs have been identified in some model systems to be upregulated in cystic fibrosis (Tarran et al., J. Gen. Physiol. 120:407-18 (2002)), providing alternative chloride conductance to compensate for missing or defective CFTR. However, CaCC activity may contribute to excess mucus secretion by epithelial cells in the lungs of patients with pulmonary diseases and disorders, such as asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, and cystic fibrosis. Excess mucus production and concomitant change in the lung environment lead to colonization by bacteria that exacerbate the pathophysiology of the diseased lung. Thus, inhibitors of CaCCs are needed treating pulmonary diseases and disorders that exhibit mucus hypersecretion.